This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. AIMS: All medications that treat attention deficit hyperactivity disorder (ADHD) attenuate the transport of dopamine (DA) and norepinephrine (NE), via the dopamine (DAT) and/or norepinephrine (NET) transporters. Trace amines have been implicated in ADHD, as the trace amine phenethylamine (PEA) is reduced in urines of ADHD male children and normalized by anti-ADHD medications, in some reports. With the underlying mechanisms unknown, we postulated that ADHD medications normalize PEA levels in ADHD children by blockade of PEA transport by the DAT or NET. METHODS: We determine whether ADHD medications (methylphenidate, (+)-amphetamine, atomoxetine, modafinil) affected (3H)PEA transport by the DAT and the NET. RESULTS: Methylphenidate was nearly 2-fold more potent at blocking (3H)PEA than (3H)DA transport by the DAT and also potently blocked (3H)PEA transport by the NET. (+)-Amphetamine was 3-fold less potent at blocking (3H)PEA than (3H)DA transport. Atomoxetine was a weak inhibitor of (3H)DA or (3H)PEA transport by the DAT and a potent inhibitor at the NET Modafinil, which occupies the DAT and the NET in vivo, was a relatively weak inhibitor of DAT transport, but was slightly more potent at blocking (3H)PEA than (3H)DA transport. Other therapeutic drugs, mazindol, nomifensine, benztropine bupropion, were 2-4 times more potent at blocking (3H)PEA than (3H)DA transport. CONCLUSIONS: Conceivably, blockade of PEA transport by anti-hyperactivity medications accounts for normalization of urinary PEA levels in ADHD male children. These results implicate trace amines, transporters and the trace amine receptor1 in the therapeutic response of ADHD medications which target DAT and NET.